PROJECT SUMMARY Mitochondria are organelles that generate most of the energy in the cell. There is a gap in our understanding of how specific mitochondrial pathways are regulated to suit tissue-specific function and metabolism. The goal of this proposed research is to fill this knowledge gap and to reveal a previously unrecognized role for a nuclear receptor ERR?-dependent transcriptional program in kidney physiology and disease. Supported by our extensive preliminary data, we hypothesize that ERR? contributes to normal kidney function and renal disease by controlling mitochondrial and renal function in cooperation with kidney-specific transcription factors. In Specific Aim 1, we will determine the essential role of ERR? in maintaining normal mitochondrial and renal function in vivo, using a novel mouse model. We will also investigate whether activation of the ERR? transcriptional program can improve kidney function in kidney disease models. In Specific Aim 2, we will determine mechanistically how ERR? regulates renal mitochondrial and functional genes, employing state-of-the-art genomic approaches. Together, these studies will have a significant impact by enhancing our understanding of tissue specific mechanisms for maintaining mitochondrial function, and revealing a novel ERR? pathway in kidney function and the potential for therapies targeting ERR?.